Multiscale Modeling of Blood Flow and Platelet Mediated Thrombosis

血流和血小板介导的血栓形成的多尺度建模

• 批准号: 9032130
• 负责人: DANNY BLUESTEIN
• 金额: $ 68.94万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9032130
• 关键词: Accounting; Address; Adhesions; Adopted; Agonist; Algorithms; Anticoagulation; Antiplatelet Drugs; Arteries; Benchmarking; Binding; Biochemical; Biology; Biomechanics; Blood; Blood Circulation; Blood Coagulation Factor; Blood Platelets; Blood Vessels; Blood flow; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cause of Death; Cereals; Cessation of life; Chemicals; Clinical; Coagulation Process; Code; Communities; Complex; Computer Simulation; Coronary Arteriosclerosis; Coupled; Coupling; Cytoplasm; Cytoskeleton; Data; Databases; Deposition; Development; Devices; Engineering; Evaluation; Event; Experimental Models; Filopodia; Growth; Health Care Costs; Hemostatic Agents; High Performance Computing; Hybrids; In Vitro; Lead; Length; Life; Liquid substance; Measurement; Measures; Mechanics; Mediating; Membrane; Methodology; Modeling; Molecular; Outcome; Patients; Pattern; Platelet Activation; Platelet aggregation; Process; Property; Proteins; Protocols documentation; Pseudopodia; Quality of life; Risk; Scheme; Series; Shapes; Software Tools; Stimulus; Stress; Surface; Technology; Therapeutic; Therapeutic Embolization; Thrombin; Thrombosis; Thrombus; Time; Tissues; Translating; Vascular Diseases; base; biomechanical model; burden of illness; computing resources; cost; design; fluid flow; hemodynamics; improved; injured; innovation; interest; men who have sex with men; microscopic imaging; molecular dynamics; molecular scale; mortality; multi-scale modeling; multidisciplinary; nanoscale; next generation; novel; particle; public health relevance; receptor; research study; response; shear stress; simulation; tool; working group

 DESCRIPTION (provided by applicant): Cardiovascular diseases remain the leading cause of death in the developed world, accounting for near 30% of all deaths globally and 35% in the US annually. Coronary artery disease (CAD) with its associated thrombotic risk is responsible for 1 of 6 deaths in the US. Coincidentally, implantable blood recirculating devices, which have provided lifesaving solutions to patients with severe cardiovascular diseases, are burdened with thrombosis and thromboembolic complications, mandating complex life-long anticoagulation. The mechanisms underlying vascular disease processes and device-related thrombotic complications are intertwined. Thrombosis in vascular disease is potentiated by the interaction of blood constituents with an injured vascular wall and the non-physiologic flow patterns generated in cardiovascular pathologies initiate and enhance the hemostatic response by chronically activating the platelets. Similarly, device thrombogenicity is induced by pathological flow fields and contact with foreign surfaces. Upon activation platelets undergo complex biochemical and morphological changes. The coupling of the disparate spatio-temporal scales between molecular level events and the macroscopic transport represents a major modeling and computational challenge, which requires a multidisciplinary integrated multiscale numerical approach. Continuum approaches are limited in their ability to cover the smaller molecular mechanisms such as filopodia formation during platelet activation. Utilizing molecular dynamics (MD) to cover the multiscales involved is computationally prohibitive. In this application we offer to develop a comprehensive state-of-the-art multiscale numerical methodology that will be able to bridge the gap between the macroscopic transport and the ensuing molecular events. We will use an integrated Dissipative Particle Dynamics (DPD) and Coarse Grained Molecular Dynamics (CGMD) approach that allows platelets to continuously change their shape and synergistically activate by a biomechanical transductive linkage chain, interact with other blood constituents and clotting factors, aggregate, and interact and adhere to the blood vessels and devices. In this multiscale model, a mechanotransduction CGMD bottom platelet activation model is embedded into a DPD blood flow top model. The dynamic stresses of the macroscale model will be interactively translated to the micro to nanoscale model of the intra-platelet associated intracellular events. The model predictions will be validated in vitro in a carefully designed set of experiments. This will be achieved according to the following specific aims: We will develop a mechanotransduction model of platelet mediated thrombosis where a top/macro-scale model of flow-induced thrombogenicity using DPD at the µm-length and ms-time scales, in which multiple flowing platelets interact with each other and blood vessel walls or devices, will be fully coupled with a bottom/micro-scale model using CGMD at the nm-length and ps-time scales, in which platelets with multiple intracellular constituents evolve during activation as platelet lose their quiescent discoid shape and filopodia grow. The top and bottom models will be interfaced such that the hemodynamics will interactively respond to platelet shape change upon activation and platelet aggregation and thrombus is formed. The effect of modulating platelet mechanical properties via antiplatelet agents will be modeled as well. All model aspects will be validated in vitro in a series of carefully designed experiments characterizing the mechanical properties of platelets and using blood flow experiments where conditions leading to flow induced platelet activation will be replicated, as well as experiments where platelet-wall and platelet device interactions will be measured and where platelets will be pretreated with modulating agents. These data will be used to fine tune the large number of model parameters involved in this multiscale simulation and for validating the model predictions. An independent 3rd party evaluation of the model credibility is also included as an integral part of the project. e will also concentrate on the development of efficient algorithms adapted for ultra-scalable large HPC clusters to reduce prohibitive computation costs, so as to bring such ambitious large multiscale simulations within the reach of the multiscale modeling community at large and enable to adopt it to other relevant modeling needs and interests. To further enable these technologies, large sharable data base will be created where software tools, numerical codes, model and experimental data and protocols will be deposited and guidance will be provided for using them. The leaders of the project will be active in various MSM consortium working groups to further disseminate the project outcomes and share them with the modeling community. The methodology proposed represents a paradigm shift in the burgeoning field of multiscale simulations and its application to solving complex clinical problems at the interface of engineering and biology. Predicting the progression of arterial thrombosis under circulation conditions, providing tools for improved pharmacological management as compared to existing empirics-based treatments, and providing a modeling tool for developing the next generation of devices with reduced thrombogenicity may lead to reduced mortality rates, improved patients' quality of life, and an overall reduction of the financial burden of the ensuing healthcare costs.

 描述（由申请人提供）：心血管疾病仍然是发达国家死亡的主要原因，每年占全球所有死亡人数的近 30%，占美国的 35%。在美国，六分之一的死亡是由冠状动脉疾病 (CAD) 及其相关的血栓形成风险造成的。巧合的是，植入式血液循环装置为患有严重心血管疾病的患者提供了挽救生命的解决方案，但也面临着血栓形成和血栓栓塞并发症的困扰，需要复杂的终生抗凝治疗。血管疾病过程和装置相关血栓并发症的机制是相互交织的。血管疾病中的血栓形成是由于血液成分与受损血管壁的相互作用而加剧的，心血管病理中产生的非生理流动模式通过长期激活血小板来启动和增强止血反应。类似地，装置血栓形成是由病理流场和与异物表面的接触引起的。激活后，血小板会经历复杂的生化和形态变化。分子水平事件和宏观输运之间不同时空尺度的耦合是一个重大的建模和计算挑战，这需要多学科集成的多尺度数值方法。连续体方法在覆盖较小分子机制（例如血小板激活过程中丝状伪足的形成）方面的能力有限。利用分子动力学（MD）来涵盖所涉及的多尺度在计算上是令人望而却步的。在此应用程序中，我们提供 开发一种全面的、最先进的多尺度数值方法，该方法将能够弥合宏观运输和随后的分子事件之间的差距。我们将使用集成的耗散粒子动力学（DPD）和粗粒分子动力学（CGMD）方法，使血小板能够不断改变其形状并通过生物力学传导连锁链协同激活，与其他血液成分和凝血因子相互作用，聚集，并相互作用并粘附到血管和装置上。在此多尺度模型中，机械转导 CGMD 底部血小板激活模型嵌入到 DPD 血流顶部模型中。宏观模型的动态应力将交互地转化为血小板内相关细胞内事件的微米到纳米模型。模型预测将通过一系列精心设计的实验在体外得到验证。这将根据以下具体目标来实现：我们将开发血小板介导的血栓形成的机械传导模型，其中使用微米长度和毫秒时间尺度的 DPD 的流动诱导血栓形成的顶部/宏观模型，其中多个流动的血小板彼此以及血管壁或装置相互作用，将与使用 CGMD 的底部/微观模型完全耦合。 nm 长度和 ps 时间尺度，其中具有多种细胞内成分的血小板在激活过程中进化，因为血小板失去其静止的盘状形状并且丝状伪足生长。顶部和底部模型将连接起来，使得血流动力学将交互地响应激活时的血小板形状变化以及血小板聚集和血栓形成。还将对通过抗血小板药物调节血小板机械特性的效果进行建模。所有模型方面都将在一系列精心设计的实验中进行体外验证，这些实验表征血小板的机械特性，并使用血流实验，其中将复制导致流动诱导血小板活化的条件，以及血小板壁和血小板的实验。 将测量血小板装置的相互作用，并用调节剂对血小板进行预处理。这些数据将用于微调多尺度模拟中涉及的大量模型参数并验证模型预测。对模型可信度的独立第三方评估也作为该项目的组成部分。我们还将专注于开发适用于超可扩展大型 HPC 集群的高效算法，以降低过高的计算成本，从而将这种雄心勃勃的大型多尺度模拟纳入整个多尺度建模社区的范围内，并使其能够应用于其他相关的建模需求和兴趣。为了进一步实现这些技术，将创建大型可共享数据库，其中将存储软件工具、数字代码、模型和实验数据和协议，并提供使用它们的指导。该项目的领导者将积极参与各个 MSM 联盟工作组，以进一步传播项目成果并与建模社区分享。所提出的方法代表了新兴的多尺度模拟领域的范式转变及其在工程和生物学交叉领域解决复杂临床问题的应用。预测循环条件下动脉血栓形成的进展，与现有的基于经验的治疗相比，提供改进药物管理的工具，并提供用于开发下一代降低血栓形成的设备的建模工具，可能会降低死亡率，改善患者的生活质量，并总体减轻随之而来的医疗费用的经济负担。